Novel process for the preparation of 17alpha-alkyl steroids



United States Patent 3,520,908 NOVEL PROCESS FOR THE PREPARATION O 17a-ALKYL STEROIDS Colin Leslie Hewett, Robert Thomas Logan, and Gilbert Frederick Woods, Glasgow, Scotland, assignors to Organon Inc., West Orange, N.J., a corporation of New Jersey No Drawing. Continuation-impart of application Ser. No. 509,625, Nov. 24, 1965. This application Oct. 26, 1967, Ser. No. 678,175

Claims priority, application Great Britain, Dec. 1, 1964,

Im. Cl. C07c 169/32 US. Cl. 260--397.45 Claims ABSTRACT OF THE DISCLOSURE CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of application Ser. No. 509,625, filed Nov. 24, 1965 now abandoned.

BACKGROUND OF THE INVENTION This invention relates to a process for the preparation of 17-alkylated steroids, and to a group of novel steroid compounds.

It is known that A --keto-pregnanes can be converted into the corresponding 17a-alkyl-20-keto-pregnanes by reduction with an alkali metal, for example lithium, and liquid ammonia followed by treatment with an alkylating agent, for examples an alkyl halide. This so-called reductive alkylation is described in inter alia I. Am. Chem. Soc. 1961, 83, p. 2965. It is probable that this reaction proceeds via the alkali metal enolate, for example the lithium enolate, for example the lithium enolate. An analogous reductive alkylation can be performed starting from a 17u-bromo or 17a-hydroxy-20 keto-pregnane.

Surprisingly it has now been found that 17-alkylation can also be carried out on an enolate salt of a 20-ketosteroid, prepared for example by reacting a A -20-ketone or a A -enol ester, such as the acetate, with Grignard reagent, by reacting it With an alkyl halide, preferably the iodide or bromide.

In addition to being novel this process has important advantages over existing reductive alkylation methods in that higher yields, usually 50-70%, are obtained. It is also now possible to prepare a novel group of 1611,1741;- dialkyl steroids which cannot readily be prepared by reductive alkylation.

3,520,908 Patented July 21, 1970 "ice SUMMARY OF THE INVENTION The novel process which constitutes one aspect of the invention may be represented by the following reaction schemes:

OMgX o l 0 OMgXz' o l RB in which "R: "R2 D I D B=an acyl group;

R==an alkyl, aryl or aralkyl group;

R =H or a lower alkyl group preferably having from 14 carbon atoms;

R =a lower alkyl group preferably having from 1-4 carbon atoms;

R =a lower alkyl group preferably having 1-4 carbon atoms, and

X and X"=a halogen atom, for example bromine or iodine.

The process according to this invention is preferably carried out by reacting either the A -enol ester, for example the acetate, or the A -20-keto-steroid with a Grignard reagent and treating the resulting A -enolate salt with an excess of an alkyl halide, usually at least four mole equivalents, and isolating the Non-substituted steroid by decomposing the Grignard complex in the usual manner. It is known, that, in order to favor formation of the required enolate salt from a A -20-keto-steroid, the reaction with Grignard reagent is preferably carried out in the presence of a suitable copper salt.

Examples of halogen compounds which may be used for the alkylation reaction include halogen derivatives of methane, ethane, propane, isopropane and butane.

The solvent used for this reaction is preferably an aprotic solvent with a low dielectric constant such as tetrahydrofuran, dioxane, an aliphatic ether, hydrocarbons such as benzene and toluene, or the alkyl halide used for the alkylation reaction.

In accordance with a second aspect of the invention, there are provided novel 17-alkyl compounds of the pregnane series which are biologically active and possess progestational and cortical activity. These compounds are 11B-hydroxy-l6,l7-dialkyl-steroids of the corticoid and progesterone type having the formula:

3 in which R =a saturated alkyl group preferably having 1-4 carbon atoms;

The acyl radical in 21-position of the above formula is that of an aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acid, such as for example of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, pi valic acid, t.butyl acetic acid, caproic acid, oenanthic acid, caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid, cyclopropylcarboxylic acid, cyclohexylcarboxylic acid, cyclopentylpropionic acid, phenylacetic acid, succinic acid, glutarie acid and tetrahydrophthalic acid, or inorganic acids such as for example phosphoric acid and sulphuric acid.

The novel llfi-hydroxy-steroids of the invention possess strong anti-inflammatory activity. This circumstance is the more surprising since the corresponding ll-ketoand lloc-hydroxy compounds are practically inactive in this respect. A great advantage of the compounds of the in-- vention is that their high anti-inflammatory activity is coupled with only low thymolytic effects, which provides a surprising and advantageous combination.

The above compounds are useful in the treatment of inflammatory conditions and allergic reactions. Administration can take place orally in the form of tablets, pills or capsules, parenterally in liquid form or topically in the form of ointments, creams or lotions, possibly in combination with other active ingredients.

Another object of this invention provides novel A steroids having the following formula:

CH2OR in which X=OH, OAcyl or a keto group,

R=hydrogen or a lower aliphatic carboxylic acid radical,

R =a saturated alkyl group having 1-4 carbon atoms,

R =hydrogen or a saturated alkyl group having 1-4 carbon atoms, and

C -C and C C may be saturated or unsaturated.

These compounds have utility as intermediates in the preparation of the corresponding 11 3-hydroxy-9a-fluorosteroids.

The novel compounds described above may be obtained from 20-keto-A -pregnene derivatives or 20-keto-pregnane derivatives, in which the 16x-position may be substituted by an alkyl group and may contain other double bonds, for example the A double bond, or hydroxyl or acyloxy groups, for example, in position 3 and/or 11, or a free protected keto group, for example an ll-keto group or a 3-alkylidene dioxy group, by introducing the 17a-alkyl substituent according to the process of the present invention. The 17a-alkyl and 16a,l7a-dialkyl derivatives of the 20-keto pregnane thus obtained may be reacted further, for example, acyloxy groups may be hydrolyzed, hydroxyl groups may be oxidized by methods known per se and additional double bonds may be introduced in a manner known per se.

The process of the present invention for the preparation of these compounds has a great advantage over other methods of alkylating at position 17 in that it is now possible to obtain a 16a,l7a-dialkyl 20-keto-pregnane compound. The existing method of preparing 16,17-disubstituted ZO-keto-compounds by reductive alkylation of a A -16-alky1-20-keto-pregnane leads to the therapeutically less important 16,8,l7oc-di-alkyl compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention is further illustrated by the following examples, which are not, however, to be regarded as limiting:

Example 1 A solution of pregna-5,17(20)-diene 313,20-diol di-acctate (7.5 g.) in ether was added to a stirred solution of methyl magnesium bromide (2 molar) in ether cc.). Solid began to precipitate half-Way through the addition and stirring was continued for five hours and then the reaction was allowed to stand at 20 C. for sixteen hours. The ether was then distilled off and replaced at an equal rate with tetrahydrofuran until the boiling point had been reached at 62 C. and the solution was complete. The cooled stirred solution was carefully treated with methyl iodide (37.5 cc.) which caused some solid to precipitate and the reaction was allowed to stand at 1820 C. with occasional stirring for twelve days. The mixture was then poured into 10% ammonium chloride solution and extracted with ether. The extract was washed with dilute hydrochloric acid, water, sodium bisulphite and water to neutrality, dried and evaporated to dryness. The gummy product was acetylated in pyridine/ acetic anhydride overnight at 20 C. and the mixture of acetates isolated via ether. The crude acetate was chromatographed on silica gel and elution with 1% ether in benzene gave a product which crystallized from methanol/methylene chloride to give 17u-methyl pregn-5-en-3B-ol-20-one acetate (4.8 g.). Hydrolysis of the acetate by refluxing with methanolic potassium carbonate for thirty minutes gave 17a-methyl pregna-5-en-3/3-ol-20-one (4.3 g.).

1.2 g. of his compound was dissolved in dry toluene (20 cc.) and cyclohexanone (6 cc.) and the solution distilled until free from Water. A solution of aluminum isopropoxide (0.66 g.) in dry toluene was added to the hot solution, which was then refluxed for thirty minutes and slowly distilled for ten minutes. The cooled solution was treated with an aqueous solution of Rochelle salt (2.5 g.) and steam distilled until no more steam volatile products distilled. The solid residue was filtered, dissolved in ether and the ether solution dried over sodium sulphate. The dried solution was run through a short column of alumina and the product crystallized from ether/hexane to give l7a-methyl-progesterone (850 mg).

Example 2 Pregn 5,17(20) diene-3B,2'0-diol diacetate (20 g.) in ether was added to a stirred solution of methyl magnesium iodide (2 molar) in ether (100 cc.). Some solid precipitated during the addition and stirring was continued for five hours after which the reaction was allowed to stand at 20 C. for fifteen hours. The ether was then gradually distilled and replaced with tetrahydrofuran, keeping the volume almost constant, until the solution was complete, by which time the boiling point had been reached, i.e., 62 C. The cooled stirred solution was treated carefully with ethyl iodide (50 cc.) and after stirring for two hours the reaction was allowed to stand at l820 C. for ten days. The mixture was then poured on to 10% ammonium chloride solution, the product extracted with ether, and the extract Washed with dilute hydrochloric acid, water, sodium bisulphite solution and then with water to neutrality. The dried extract was evaporated to give a gum which was acetylated overnight in pyridine/acetic anhydride at 20 C. and the acetate isolated via ether. The

product was chromatographed on silica gel and elution with 1% ether in benzene gave a solid which crystallized from methanol to give 17a-ethyl pregn--en-3fi-ol-20-one acetate (5.9 g.).

In accordance with the method described in the previous example this compound has been converted into l7a-ethyl-progesterone.

In an analogous manner there has been prepared 60:, 17ot-dimethyl-progesterone, 17a-propyl-desoxycorticosterone acetate and 17a-methyl-lIB-hydroxy-progesterone.

Example 3 A solution of the magnesium A -enolate salt of 16amethyl pregn 5 en-SB-ol-ZO-one, prepared by treating pregn-S,16-dien-3fi-ol-20-one (32 g.) with a solution of methyl magnesium bromide (0.96 molar) in tetrahydrofuran (900 cc.) in a nitrogen atmosphere in the presence of cuprous bromide (2.5 g.), was treated carefully with methyl iodide (200 cc.) with cooling and after stirring at room temperature for five hours the reaction was allowed to stand for five days. The product was isolated by decomposing the Grignard complex in ammonium chloride solution and then extracting with either. The washed and dried extract was evaporated and the product crystallized from methanol to give 16a-17a-dimethy1 pregn-5-en-3 3-ol-20-one (17 g.), which has been converted into 16a,17a-dimethyl-progesterone according to the method as described in Example 1.

In an analogous manner there has been prepared 160cethyl-l7a-methyl-progesterone, 16a-butyl-17a-methyl-progesterone, 16a butyl-17u-methyl-progesterone, 16a-methyl 17a ethyl-progesterone, 6a,16a,17a-trimethyl-progesterone, 6a-methyl-16a-ethyl-l7a-methyl-progesterone, 7a, 16a,l7a-trimethyl-progesterone and 7a,16u-dimethyl-16aethyl progesterone.

Example 4 A stirred solution of methyl magnesium bromide in THF (56 cc.; 0.95 M) was cooled to 5-7 C. and treated with a suspension of cupric acetate (400 mg.) in THF in an atmosphere of nitrogen and after minutes a solution of pregna-S,16-diene-3p,21-diol-20-one diacetate (5 g.) in THF was added slowly keeping the temperature of the reaction below 10 C.

Stirring was continued and after 1.5 hours, the cooling bath was removed and the solution allowed to Warm to room temperature for a further 1.5 hours. The solution was again cooled to 7 C. and methyl iodide (100 cc.) was added cautiously at first keeping the temperature below 10 C. When addition of the methyl iodide was complete the solution was allowed to warm to room temperature and then it was heated under reflux for 3 days. The solution was then distilled to remove the methyl iodide, until the boiling point reached 63 C. and the cooled residue was poured into an ice cold solution (300 cc.) of ammonium chloride (10 g.) and sodium thiosulphate (2.5 g.). The product was extracted with ether and the extract washed with 5% ammonium chloride solution, water, 2 N HCl, and then with water to neutrality. The dried extract was acetylated overnight with pyridine/ acetic anhydride at room temperature and the acetylated product isolated via ether. The dried extract was diluted with hexane and after the ether had been removed by distillation the residual hexane solution was passed through a short column of alumina. The combined eluate and washings were evaporated to a low bulk to give a crude product (3.6 g.) which was crystallized from methanol to give 16oz,17a-dimethyl pregn-5-ene-3 3,21-diol-20-one diacetate (2.4 g.).

The corresponding free 3fi,21-diol was converted into 16a,17a-dimethyl-desoxycorticosterone by Oppenauer oxidations; subsequent treatment with acetic anhydride and pyridine gave the corresponding 2l-acetate.

In a similar manner 16u-ethyl-17a-methyl-desoxycorticosterone; l6a-propyl-17aethyl-desoxycorticosterone;

16a-dimethyl-l7a-ethyl-desoxycorticosterone; 6a,16u,17oztrimethyl desoxycorticosterone; 16a,l7 x dimethyl-corticosterone; 6a,16a,17a-trimethyl-corticosteroneand their 21-acetates have been prepared.

Example 5 A stirred solution of 0.9 M methyl magnesium bromide (250 cc.) in tetrahydrofuran was treated in an atmosphere of nitrogen with a solution of cuprous bromide (2.64 g.) in dry tetrahydrofuran, and a solution of 3fi,11a-dihydroxy-A -5apregnane-ZO-One diacetate (15 g.) in tetrahydrofuran was added over about 15 minutes keeping the temperature at 20-25 C. with water cooling. The mixture was stirred at 20 C. for 6 hours by which time reaction was complete (no U.V. absorption at 240 m.). Methyl iodide cc.) twice distilled over P 0 was then added cautiously with cooling and after the addition was complete the stirred mixture was heated under reflux for 24 hours with rigorous exclusion of moisture. The mixture was evaporated almost to dryness under reduced pressure to remove methyl iodide and the brown residue was treated with 1 liter of a solution containing 5% ammonium chloride and 2 /z% sodium thiosulphate. The solid was filtered and washed with dilute HCl and water and dissolved in methylene chloride. The dried extract was filtered through a short column of alumina and washed through with more methylene chloride. The combined eluates were evaporated to dryness and the product was acetylated in pyridine (60 cc.) and acetic anhydride (30 cc.) overnight at 20 C. The crude diacetate was crystallized from methanol to give 3/3,11a-dihydroxy-16a, 17a-dimethyl-5a-pregnan-20-one diacetate (11 g.).

In a similar manner a series of A -20-oxo-pregnenes were reacted to give the corresponding l6u,17a-dimethyl derivatives. The following are given as examples and are not to be construed as limiting:

3u,11,8 dihydroxy A 5B -pregnen 20 one 3- acetate to give 304,113 dihydroxy 1611,170: dimethyl- 55 pregnan 20 one 3 acetate; 313,125 dihydroxy- A 50c pregnen 20 one diacetate to give 343,125- dihydroxy l6oc,17a dimethyl 5a pregnane 20 one diacetate; 3,8 hydroxy A 50c pregnene 11,20 dione acetate to give 313 hydroxy 16a,l70t dimethyl- 5oz pregnane 11,20 dione acetate; 3oz hydroxy A 5}? pregnene 11,20 dione acetate to give 3oz hydroxy 16a,17a dimethyl 5B pregnane 11,20 dione acetate; 355a dihydroxy 6/3 methyl A 50c pregnene 20 one 3 acetate to give 3,8,5a dihydroxy- 6B,l6a,17oc trimethyl 5a pregnane 20 one 3 acetate; 3/3 hydroxy A 5oz pregnadien 20 one acetate to give 3 8 hydroxy :,170: dimethyl-A 5oz pregnene 2O one acetate; 30: hydroxy -A 5B pregnadien 20 one acetate to give 304 hydroxyl6a,17a dimethyl A901) 5B pregnan 20 one acetate; 3B hydroxy A pregnadien 20 one acetate to give 35 hydroxy l6u,17x dimethyl A pregnen- 20 one acetate; 3,3,1lfl dihydroxy A pregnadien- 20-one acetate (prepared by known methods from ll-keto tigogenin) to give 36,1lfl-dihydroxy-l6a,17a-dimethyl-A pregnen-ZO-one acetate.

Example 6 35,11 dihydroxy A 5a pregnene 20 one diacetate (4 g.) was reacted exactly as described in Example 1 except that after the initial reaction with methyl magnesium bromide, dry distilled ethyl iodide instead of methyl iodide was used for the second part of the reaction. The crude acetylated product was fractionally crystallized from methanol to give 313-1lot-dihydroxy-16a-methyl-17aethyl-5a-pregnan-20-one diacetate (1.75 g.).

In a similar manner the following compounds were prepared:

3,8 hydroxy 16oz methyl 17oz ethyl A pregnene- 20-one acetate.

30:,115 dihydroxy 16a methyl 17a ethyl B- pregnan-ZO-one 3-acetate.

3,8,123 dihydroxy 16a methyl 17o: ethyl 50cpregnane-ZO-one diacetate.

3,8 hydroxy 16oz methyl 17cc ethyl 5 nane-11,20-dione acetate.

30c hydroxy 16a. methyl 17a ethyl 5/3 pregnane-11,20-dione acetate.

35,5u dihydroxy 6,8,16a dimethyl 17a ethyl 5apregnane-ZO-one 3-acetate.

3B hydroxy 16oz methyl 17a ethyl A 50cpregnene-ZO-one acetate.

30c hydroxy 16cc methyl 17a ethyl N 5B- pregnene-ZO-one acetate.

preg- Example 7 3B,11a dihydroxy A 50c pregnene 20 one g.) in dry tetrahydrofuran was added in an atmosphere of nitrogen over minutes to a stirred solution of 0.8 N ethyl magnesium bromide (150 cc.) in dry tetrahydrofuran to which has been added a solution of cuprous bromide (1.58 g.) in tetrahydrofuran, keeping the temperature below C. with water cooling. The mixture was stirred for 16 hours at 20 C. by which time no A 20-ketone remained in the solution (U.V. absorption of a sample). Methyl iodide (150 cc.) twice distilled over P 0 was then added cautiously with cooling and the stirred mixture was heated under reflux for hours with rigorous exclusion of moisture. The mixture was then evaporated almost to dryness under reduced pressure to remove the methyl iodide and the residue was treated with 700 cc. of a solution containing 5% ammonium chloride and 2 /2% sodium thiosulphate. The solid was filtered, washed with dilute HCl and water, dissolved in methylene chloride and the dried extract was filtered through a short column of alumina. The eluate and methylene chloride washings were combined and evaporated to dryness and the residue was acetylated overnight at room temperature in pyridine (400 cc.) and acetic anhydride (20 cc.). The crude diacetate was fractionally crystallized from methanol and acetone/hexane to give 35,110L-dlhYdI'OXY- 16a ethyl 17a methyl c pregnan 2O one diacetate (6.2 g.).

The following compounds were prepared in a similar manner:

35 hydroxy 16a ethyl 17oz methyl A pregnene- 20-one acetate.

35 hydroxy 16a ethyl 17a methyl 5a pregnane-11,20-dione acetate.

3a hydroxy 16a ethyl 17a methyl 5/8 pregnane-l 1,20-dione acetate.

3u,11fl dihydroxy 16oz ethyl 17a methyl 5,8- pregnan-ZO-one 3-acetate.

3,8,12,51 dihydroxy 16a ethyl 17a methyl 5apregnan-ZO-one diacetate.

3oz hydroxy 16o: ethyl 17cc methyl A 5 3- pregnene-ZO-one acetate.

3,8 hydroxy 16a ethyl 17a methyl A 5apregnene-ZO-one acetate.

3fi,5a dihydroxy 6,6,l7a dimethyl 16a ethyl 50cpregnane-ZO-one 3-acetate.

Example 8 A hot solution of 38,1lot-dihydroxy-16oc,Not-dimethyl- 5u-pregnane-20-one diacetate (20 g.) in methanol (100 cc.) was treated under nitrogen with a solution of potassium hydroxide (20 g.) in water (9 cc.) and methanol (100 cc.), and the mixture was heated under reflux for 2 hours. The solution was cooled and treated with acetic acid (20 cc.) and water (200 cc.) and the solid was filtered and washed with aqueous methanol and water to give 35,110: dihydroxy 16oz,17a-dimethyI-Swpregnan-ZO-one (15.8 g.).

The corresponding diacetates were hydrolyzed in a similar manner to give the following compounds:

3 [3,1 1a-dihydroxy-l6a-methyl-17a-ethyl-5ot-pregnan- 20-one 33,11a-dihydroxyd6a-ethyl-17a-methyl-5a-pregnan- 20-one Example 9 A stirred suspension of 313,110c-dihydI'OXy-l6a,l7udlmethyI-Sa-pregnan-ZO-One (15 g.) in methanol (190 cc.) at 30 C. was treated with 4 N methanolic HBr (3.65 cc.) and then dropwise with bromine (2.25 cc.) over 2-3 hours at such a rate that the solution did not color up. After approximately 2 hours, solution was complete and stirring was continued for 15 minutes after complete addition of the bromine. 10% aqueous sodium sulphite (5.75 cc.) was added to remove traces of bromide (ve test with starch/KI paper) and a solution on 10% aqueous sodium acetate cc.) followed by water (750 cc.) was added solwly with stirring, and a solid seed of the product was added. After standing for 18 hours the prodnot was filtered, washed with water and dried in vacuo at a low temperature to give 3B,l1u-dihydroxy-16a,l7cc-dimethyl-21-bromo-5a-pregnan-20-one (18.6 g.).

In a similar manner the following 160t,17OL-dlalkyl-21- bromo compounds were prepared:

3u,l.l,8 dihydroxy 1604,17oc dimethyl 21 bromo 5/8-pregnane-20-one.

3B,11,B dihydroxy-16a,17a-dimethyl 21 bIOIIIO-Sapregnan-ZO-one.

30:,115 dihydroxy 9a fluoro 16cc,17oc dimethyl 21-bromo-5fl-pregnan-20-one.

3,8,11,8 dihydroxy c fluoro 16a,l7a dimethyl 21-bromo-5a-pregnan-20-one.

3fi,l1oc dihydroxy 16oz methyl 17a ethyl 21 bromo-5a-pregnan-20-one.

3fi,110t dihydroxy 16a ethyl 170:. methyl 21 bromo-5a-pregnan-20-one.

3[:i,5a,l1B trihydroxy 6,8 fluoro :,170; dimethyl-21-bromo-5a-pregn-an-20-one.

Example 10 313,110: dihydroxy l6u,17oc dimethyl 21 bromo Sa-pregnan-ZO-one (30 g.) was dissolved in a filtered solution of silver acetate (17.4 g.) in pyridine (160 cc.) and allowed to stand at 20 C. for 64 hours. The solution was poured into ice made 2 N with respect to hydrochloric acid and the solid product filtered and extracted several times with ethyl acetate. The washed and dried extract was evaporated to dryness to give the crude product (32 g.) which was purified by dissolving it in acetone, treating the solution with animal charcoal and filtering through a column of alumina. Evaporation of the eluate and washing gave 3,8,11a,2l-trihydroxy-l6a,17a-dimethyl-5a-pregnan-20-one 21-acetate (27 g.).

In a similar manner the following 21-acetoxy compounds were prepared:

3a,11/i,21 trihydroxy 16a dimethyl 5,8 pregnan 20-one 21-acetate.

313,115,21 trihydroxy 16a,17u dimethyl 5a pregnan-ZO-one 21-acetate.

3,8,12;3,21 trihydroxy 16a,17 x dimethyl 5oz pregnan-20-one 21-acetate.

3a,11;8,21 trihydroxy 16ot,170c dimethyl 5B pregnan-20-one 21-acetate.

3,3,11oz,21 trihydroxy 16oz methyl 17a ethyl 5u-pregnan-20-one ZI-acetate.

3B,11oc,21 trihydroxy 16a ethyl 17a methyl Su-pregnan-ZO-Qne 21-acetate.

3B,21 dihydroxy 16a,17a dimethyl A 5a pregnan-ZO-one 21-acetate.

3oz,2l dihydroxy 16a,17u dimethyl A B pregnan-20-one 21-acetate.

3a,llfi,2l trihydroxy 16oz Sfi-pregnan-ZO-one 21-acetate.

35,116,21 trihydroxy 16a 5a-pregnan-20-one 21-acetate.

35,115,21 trihydroxy 16oz 5a-pregnan-20-one 21-acetate.

30c,l1/3,21 trihydroxy 16a 5,Bpregnan-20-one 21-acet-ate.

3/9,5o;,11fl,21 tetrahydroxy 65 fluoro 16a,l7a di- IIIElhYI-SwPI'GgHaH-ZO-OHB 21-acetate.

3B,5ot,11fl,21 tetrahydroxy 6fi,l6ot,17oz trimethyl Sa-pregnan-ZO-one 21-acetate.

3ot,21 dihydroxy 16a ethyl 17a methyl Agul) Sfi-pregnan-ZO-one 2l-acetate.

30:,21 dihydroxy 16a methyl 17a ethyl A 5,8-pregnan-20-0ne 21-acetate.

methyl 17a ethyl methyl 17cc ethyl ethyl 17a methyl ethyl 17a methyl Example 11 A stirred solution of 3,8,11oz,21-trihydroxy-16a,17x-dimethyI-Su-pregnan-ZO-One 21-acetate g.) in t-butanol (162 cc.) and pyridine (9.5 cc.) at 45 C. was treated under nitrogen with N-bromo-succinimide (7.1 g.) and after 2 hours more N-bromo-succinimide (2.4 g.) was added and stirring continued for another hour. The stirred mixture was cooled to C. and treated with acetic acid (47.5 cc.) and zinc (12.9 g.) which was added slowly keeping the temperature below C. Charcoal (0.7 g.) was then added and the mixture was stirred overnight at 25 C. The filtered solution was concentrated to 100 cc. under reduced pressure and added at 5 C. to 400 cc. of ice water containing concentrated sulphuric acid (4 cc.). The solid was filtered, washed and dried to give 1loc,21 dihydroxy 160:,1706 dimethyl 5a pregnane 3,20-dione 21-acetate (8.2 g.).

The following 3-oxo compounds were prepared in a similar manner:

11a-hydroxy-16a,17ot-dimethyl-5a-pregnane-3,20-dione.

11B-hydroxy-16a,17a,dimethyl-5B-pregnane-3 ,20-dione.

11a hydroxy 16a methyl 17a ethyl 5a pregnane-3,20-dione.

11oz hydroxy 16a ethyl 17a methyl 5o: pregnane-3,20-dione.

116,21 dihydroxy l6oc,l7ot dimethyl 5p pregnan 3,20-dione 21-acetate.

12,8,21 dihydroxy 160c,l7a dimethyl 50c pregnan 3,20-dione 21-acetate.

11fi,21 dihydroxy 16a,17a dimethyl 5oz pregnan 3,20-dione 21-acetate.

1111,21 dihydroxy 16oz methyl 17a ethyl 5o:- pregnan-3,20-dione 21-acetate.

110:,21 dihydroxy 16a ethyl 17a methyl 5apregnan-3,20-dione 21-acetate.

21 hydroxy 16a,17a dimethyl A 50c pregnen-3,20-dione acetate.

21 hydroxy 16u,17 x dimethyl A901) 5/3 pregnen-3,20-dione acetate.

11,6,21 dihydroxy 16oz methyl 17a ethyl 5,8- pregnan-3,20-dione 21-acetate.

1113,21 dihydroxy 16a methyl 17oz ethyl 5ozpregnan-3,20-dione 21-acetate.

11 6,21 dihydroxy 16a ethyl 17cc methyl 5apregnan-3,20-dione 21-acetate.

11,8,21 dihydroxy 16cc ethyl 17oz ethyl Sflpregnan-3,20-dione 21-acetate.

5a,11,6,21 trihydroxy 6fi,16a,l7u trimethyl 5apregnane-3,20-dione 21-acetate.

5a,11{3,21 trihydroxy 6B fluor0-16u,17ot-dimethyl- 5a-pregnane-3.,20dione 21-acetate.

5u,11,B,21 trihydroxy 6B fiuoro 16zx,l7ot dimethyl-5u-pregnane-3,20-dione 21-acetate.

1 0 Example 12 A stirred solution of 11a,21 dihydroxy 16a,17a dimethyl-5a-pregnane-3,20-dione 21-acetate (8.2 g.) in pyridine (16.5 cc.) was cooled in an ice bath and treated over 20 minutes with p-toluene sulphonyl chloride (7.4 g.). The solution was kept at 0-4 C. for 48 hours and then ice water (16.5 cc.) was added at such a rate that the temperature remained below 25 C. The solid was filtered, washed with 30% aqueous pyridine and water and then dried in vacuo at 40 C. The crude product in acetone was purified with animal charcoal and crystallization from aqueous acetone gave 1la,21-dihydroxy- 16a,17a-dimethyl 5a pregnane 3,20-dione 11-tosylate-21-acetate (5.7 g.).

The following lla-tosyloxy compounds were prepared in a similar manner:

11a hydroxy 160:,170: dimethyl 5a pregnanc- 3,20-dione ll-tosylate.

11a,21 dihydroxy 16a methyl 17oz ethyl 5ozpregnane-3,20-dione 11-tosylate 2l-acetate.

1111,21 dihydro 160: ethyl 17a methyl 5ozpregnane-3,20-dione ll-tosylate 2l-acetate.

Example 13 A stirred solution of 110:,21 dihydroxy 1611,1711- dimethyl 5a pregnane 3,20 dione 11m tosylate 21- acetate (3.73 g.) in methylene chloride (26 cc.) and acetic acid (45.6 cc.) was cooled to 5 C. and treated with a solution of 4 N HBr in acetic acid (3.33 cc.). Bromine (0.69 cc.) in acetic acid (8.3 cc.) was added slowly over approximately 35 minutes at such a rate that the solution remained almost colorless. Stirring was con tinued for a further 30 minutes at 15 C. by which time no bromine remained (ve reaction with starch-iodide paper). A solution of sodium acetate (5.2 g.) in water (10 cc.) was added and after 10 minutes stirring the solution which was acid to Congo red was poured into 200 cc. of water and shaken thoroughly. The product was isolated by extraction with methylene chloride and the washed and dried extract was evaporated to dryness under vacuum and the residue was dissolved in dioxan (10 cc.) and poured slowly into stirred ice water cc.). The solid was filtered, washed and dried to give 25,45- dibromo :,21 dihydroxy 16u,17m dimethyl 50cpregnane-3,20-dione ll-tosylate 21-acetate (4.9 g.).

In a similar way the following 2,4-dibromo compounds were prepared:

25,45 dibromo 11a,21 dihydroxy 16oz methyl- 17ot-ethyl-5a-pregnane-3,20-dione 11-tosylate-21-acetate.

25,45 dibromo 110:,21 dihydroxy 16oz ethyl l7ocmethyl-5a-pregnane-3 ,20-dione 1 1-tosylate-21-acetate.

25,45 dibromo 16,17u dimethyl 21 hydroxy- A -5a-pregnene-3,ZO-dione acetate.

Example 14 25,45 dibromo 110;,21 dihydroxy 16a,17a dimethyl 5a pregnane 3,20 dione 11 tosylate 21- acetate (4.9 g.) was added to a mixture of lithium bromide (3.5 g.) and dry calcium carbonate (7.0 g.) in dimethyl formamide (300 cc.) and the mixture was stirred at 135 C. for 5 hours. It was then concentrated to 200 cc. under vacuum at 75 C. and poured with stirring into ice water (1600 cc.), made acid with hydrochloric acid and allowed to stand overnight. The solid was filtered, washed and dried and the product was extracted from some inorganic material with ether to give on evaporation of the extract 16u,17a dimethyl 21 hydroxy- A pregnatriene 3,20 dione ZI-acetate (2.1 g.).

In a similar way the following A trienes were prepared:

21 hydroxy 16a methyl ethyl A pregnatriene-3,20-dione acetate.

21 hydroxy 16m ethyl 17a methyl A pregnatriene-3,20-dione acetate.

1 1 Example 15 A stirred solution of 160:,170t dimethyl 21 hydroxy- A1-4,9(11) pregnatriene 3,20 dione 21 acetate (2.6 g.) in dimethyl formamide (15.2 cc.) was treated dropwise at C. with 70% perchloric acid (0.52 cc.) keeping the temperature below 20 C. N-bromo-succinimide (1.67 g.) was added over 10 minutes with the exclusion of light, and stirring was continued for 4 hours at 30 C. The reaction was cooled to 2024 C. and sodium sulphite (0.52 g.) in water (0.5 cc.) added, and the mixture poured into ice water (200 cc.). The solid was filtered, washed and dried under vacuum to give 9a-bromo- 115,21 dihydroxy 16a,17u dimethyl A pregnadiene-3,20-dione ll-formate ZI-acetate (3.1 g.).

In a similar manner the following 9a-bromo-l15-formyloxy compounds were prepared:

9a bromo 115 hydroxy l6oc,l7oc dimethyl A pregnadiene-3,20-dione ll-formate.

90c bromo 115,21 dihydroxy 16a methyl 17aethyl-A -pregnadiene-ZO-one ll-formate-Zl-acetate.

90c bromo 115,21 dihydroxy 1600 ethyl 17amethyl-A -pregnadiene-20-one 11-f0rmate-21-acetate.

6a fluoro 9oz bromo 115,21 dihydroxy 16a,17udimethyl A pregnadiene 3,20 dione ll-formate 21-acetate.

6a,16a,17a trimethyl 9a bromo 115,21 dihydroxy A pregnadiene 3,20 dione 11 formate 21- acetate.

Example 16 A stirred solution of 9ot-bromo-l15,21-dihydroxy-16a, 17a dimethyl A -pregnadiene-3,20-dione ll-formate 21-acetate (3.1 g.) in tetrahydrofuran (25.6 cc.) and methanol (21.4 cc.) at C. was treated under nitrogen with N sodium methoxide in methanol (7.75 cc.). After stirring for 30 minutes at C. the solution was acidified to pH 6 with acetic acid and poured into a mixture of chloroform (20 cc.) and water cc.). The product was isolated via chloroform and crystallized from acetone to give 95,115-oxido-16a,17a-dimethyl-21 hydroxy A pregnadiene-3,20-dione (1.4 g.). Acetylation in pyridine and acetic anhydride at room temperature gave the 21- acetate.

In a similar manner the following 95,115-oxides and their acetates were prepared:

95,115 oxido 16cc methyl-17u-ethyl-2l-hydroxy- A -pregnad'iene-3,20-dione.

95,115-oxido-16a-ethy1-17a methyl 21 hydroxy- A -pregnadiene-3,20-dione.

95,115 oxido-16a,l7ot-dimethyl-A -pregnadiene-3,20- dione.

Got-fluoro 95,115 oxido 16u,17adimethyl-21-hydroxy-A -pregnadiene-3,20-done.

6a,16a,l7ot trimethyl 95,115 oxido 21 hydroxy- A -pregnadiene-3,20-dione.

Example 17 A solution of 95,115 EPOXY-160a,I7u-dim6tl1Yl-21-hY- droxy-A -pregnadiene-3,20-dione (2.5 g.) in chloroform (12 cc.) was added to a solution of anhydrous hydrogen fluoride (6.5 g.) in tetrahydrofuran (10 cc.) and chloroform (4.5 cc.) at 25 C. to C. and washed with chloroform (14 cc.). The resulting solution was kept in ice at 0 C. for 4 hours, after which the mixture was slowly added with stirring to a solution of potassium carbonate (25 g.) in ice Water and stirring was continued for 15 minutes. acetic acid was added until the aqueous phase was pH 6 and the mixture was then distilled under vacuum to remove the chloroform. The residue Was cooled to 5 C. and the solid filtered, washed and dried. The crude product was treated with chloroform (2.5 cc.) by swirling for one hour and then cooled to 10 C. and the solid filtered to give 9u-fluoro-115,21-dihydroxy-16u, 17a-dimethyl-A -pregnadiene-3,20-dione (1.8 g.).

In a similar manner the following 9a-fluoro-115-hydroxy compounds were prepared:

c fluoro hydroxy l6oz,17ot-dimethyl-A pregnadiene-3,20-dione.

9a fluoro 115,21-dihydroxy-16a-methyl-17a-ethyl- A -pregnadiene-3,20-dione.

9a-fluoro-115,21 dihydroxy a ethyl-17wmethyl- A -pregnadiene-B,20-dione.

6a,9ot difluoro-115,21 dihydroxy-16u,17u-dirnethyl- A -pregnadiene-3,20-dione.

6a,16zx,17ot trimethyl-9u-fluoro 115,21-dihyd'roxy- A -pregnadiene-3,20-dione.

Example 18 110:,21 dihydroxy l6a,17a-dimethyl-5a-pregnane-3, 20-dione ll-tosylate 21-acetate (3 g.) was carefully added to stirred collidine (10 cc.) almost at the boil. The solution was heated under reflux for 30 minutes, cooled to 50 and slowly poured into a stirred mixture of ice and hydrochloric acid. After 30 minutes the solid was filtered from the acid solution, washed with 5 N hydrochloric acid, then with warm water to neutrality and dried to give 21 hydroxy 16oc,17oc dimethyl-A -5 a-pregnene- 3,20-dione acetate (2.05 g.).

In a similar manner the following M -compounds were prepared:

16a,17a-dimethy1-A -5u-pregnene-3,20-dione.

21 hydroxy-16a methyl 17a-ethyl-A -5u-pregnene-3,20-dione acetate.

21 hydroxy-16a-ethyl-17ot-methyl-A 5a pregnene-3,20-dione acetate.

Example 19 A solution of 21 hydroxy-16a,17a-dimethyl-A -5apregnene-3,20-dione acetate (6 g.) and dichlorodicyanobenzoquinone (9.5 g.) in dioxan (60 cc.) was heated under reflux for 18 hours. The mixture was filtered and the filtrate evaporated to dryness and extracted several times with benzene. The combined benzene extracts were concentrated and passed down a short column of alumina and washed through with benzene. The combined eluates were evaporated to dryness and the residue was crystallized from acetone to give 21-hydroxy-16u,Hot-dimethyl- A -pregnatriene-3,20-dione acetate (2.9 g.).

The following A -trienes were prepared in a similar manner:

16a,17a-dirnethyl-A -pregnatriene-3,20-dione.

21 hydroxy-16u-methyl-17a-ethyl-A -pregnatriene-3,20-dione acetate.

21 hydroxy-16u-ethyl-17ot-methyl-A -pregnatriene-3,20-dione acetate.

Example 20 A stirred solution of 35 hydroxy-16a,17u-dimethyl- A -pregnene-20-one (10 g.) in tetrahydrofuran (350 09.) was heated vigorously under reflux with cupric bromide (15.5 g.) for 4 hours. The cooled solution was filtered from cuprous bromide which was washed with a little tetrahydrofuran and the combined filtrate and washings were concentrated at 20 under vacuum and then carefully diluted with water to give a slightly tacky solid which was separated by filtration and washed with water. A solution of the solid in benzene was washed neutral with water, dried and passed through a column of silica gel (40 g.) and washed through with benzene. The combined eluates were evaporated to dryness at 2025 C. under vacuum and the residue was crystallized from methylene chloride/methanol to give 35 hydroxy-16a, 17a dimethyl 21 bromo-A -pregnen-20-one (6.5 g.).

The following 21-bromo compounds were prepared in a similar manner:

35 hydroxy 160C,1706 dimethyl 21 bromo A Sa-pregnen-ZO-Qne.

3a hydroxy 16u,17u dimethyl 21 bromo A 55-pregnen-20-one.

3oz hydroxy 16cc ethyl 17a methyl 21 bromo- A -5fl-pregnen-20-one.

30c hydroxy 16oz methyl 17a ethyl 21 bromo- A -5,8-pregnen-20-one.

Example 21 A stirred solution of 115,21 dihydroxy 16a,17a dimethyl 5B 3,20 dione 21 acetate (2.32 g.) in methylene chloride (23 cc.) and acetic acid (42.5 cc.) was cooled to 5 C. and treated with a solution of 4 N HBr in acetic acid (3.33 cc.). Bromine (0.345 cc.) in acetic acid (8.3 cc.) was added slowly over approximately 35 minutes at such a rate that bromine was not allowed to accumulate in the solution. Stirring was continued for a further 30 minutes at 15 C. by which time the solution was bromine free (-ve reaction with starch/KI paper). Sodium acetate (5.2 g.) in water cc.) was added and after stirring for 10 minutes the solution was poured into water (200 cc.) and shaken thoroughly. The product was extracted with methyl chloride and the washed and dried extract wasevaporated to dryness under vacuum. The residue was dissolved in dioxan (10 cc.) and slowly poured into stirred ice water (100 cc.) and the solid which formed was filtered, washed and dried to give 4.-bromo-11fi,21- dihydroxy 16a,17a dimethyl 5,8 pregnan 3,20 dione 21-acetate (2.6 g.).

In a similar manner the following 3-oxo-4-bromo-5ppregnanes were prepared:

45 bromo 11,8,21 dihydroxy 16cc methyl 17aethyl-5fl-pregnan-3,20-dione 21-acetate.

4E bromo 11,8,21 dihydroxy 16a ethyl 17amethyl-5fl-pregnan-3,20-dione 21-acetate.

4E bromo 16a,17a dimethyl 21 hydroxy 5,8- pregnane-3,1 1,20-trione 21-acetate.

Example 22 Lithium bromide (18 g.) and lithium carbonate (18 g.) were added to dimethylformamide (200 cc.) and the stirred mixture was heated to 95 C. under an atmosphere of nitrogen. 4.5 bromo 115,21 dihydroxy 160:,17otdimethyl 5,3 pregnan 3,20 dione 21-acetate (18 g.) was added over 5-10 minutes, and the mixture was maintained under nitrogen at 95 for 5 hours with stirring. The mixture was then poured into a mixture of water (1.25 1.), ice (500 g.) and acetic acid (35 cc.) and agitated for some time after which the solid was filtered and the precipitate washed neutral and free from organic material with water. The dried crude product was crystallized from alcohol/ methylene chloride to give 1113,21 dihydroxy 16a,17adimethyl A pregnene 3,20 dione 21 acetate (10.4 g.).

The free 21-hydroxy compound was prepared by treating a solution of the 21-acetate in methanol with 1.1 molar equivalents of sodium hydroxide at 510 in an atmosphere of nitrogen.

A variety of 21-esters were prepared from the 21-hydroxy compound by reaction using known procedures with the appropriate acylating agent. These included the formate, propionate, isobutyrate, hexaoate, phenylpropionate, pivalate, isovalerate, decanoate and hemisuccinate.

Reaction of the free hydroxy compound with pyridine sulphur trioxide complex gave the pyridinium salt of the 21-hernisulphate ester. This was readily converted by reaction with the appropriate inorganic salt to the sodium, potassium and calcium salts of the 21-hemisulphate ester.

In a similar manner, the following compounds were prepared and hydrolyzed to the corresponding free 21- hydroxy compounds which were then converted to the same 21-esters:

16:1,170; dimethyl 21 hydroxy A pregnene 3,11, 20-trione acetate.

11,8,21 dihydroxy 16a methyl 17a ethyl A pregnene-3,20-dione 21-acetate.

11 3,21 dihydroxy 16oz ethyl 17oz methyl A pregnene-3,20-dione 21-acetate.

1 4 Example 23 A solution of 35,11 8 dihydroxy 160:,170: dimethyl- A pregnen 20 one (11 g.) in isopropyl alcohol (600 cc.) was treated with In. chloroperbenzoic acid (13.5 g.) and the solution was allowed to stand at 18 C. for 30 hours. Sodium bisulphite was added to destroy excess peracid and then a slight excess of sodium bicarbonate was added, followed by excess water. The solid was filtered, washed thoroughly with water and dried in vacuo to give after one crystallization from aqueous methanol 35,11 8 dihydroxy 5d,6d. epoxy 16a,17a dimethyl- 5ot-pregnan-20-one (6.5 g.).

Example 24 Anhydrous hydrogen fluoride (20 g.) was passed into a solution of 313,115 dihydroxy Sot,6u oxido 16a,l7adimethyl 50c pregnan 20 one (8.9 g.) in methylene chloride cc.) while the temperature was maintained at 04 C. The mixture was stirred vigorously for two hours and then slowly added to a stirred solution of potassium carbonate 85 g.) in ice water and stirring was continued for 15 minutes. The aqueous phase was made pH 6 by addition of 50% acetic acid and the mixture was then distilled under vaccum to remove the methylene chlorine. The solid which formed was filtered, washed and dried, and purified by swirling with a little chloroform to give 3fl,5u,11,8 trihydroxy 6,8 fluoro 16a,l7a dimethyl- 5a-pregnan-20-one (5.2 g.).

Example 25 A solution of 313,115 dihydroxy 511,60: oxido a, a dimethyl 5a pregnan 20 one (0.96 g.) in benzene (50 cc.) was added to a solution of methyl magnesium bromide (prepared from 0.7 g. of magnesium) in ether and the ether was allowed to distill until the boiling point reached 788'0 C., and the mixture was then heated under reflux for a total of 3 hours. The reaction mixture was then poured into ice containing hydrochloride acid and the product was isolated via methylene chloride and crystallized from acetone/diisopropyl ether to give 3 3,50, 11,8 trihydroxy 6/3,160c,17rx trimethyl 5a pregnan- 20-one (0.65 g.).

Example 26 501,115,21 trihydroxy 65 fluoro 1601,1711 dimethyl 5oz pregnane 3,20 dione 21 acetate (2 g.) was heated under reflux for 1.5 hours in acetic acid (50 cc.) and the product, a mixture of the A -6u and 6/8-fiuoro compounds was isolated by addition of water. The crude dried product was dissolved in 1% KOH in methanol (40 cc.) and allowed to stand at 15-20" C. for 2 hours in an atmosphere of nitrogen. The solution was then neutralized with acetic acid and concentrated under reduced pressure to give 60: fluoro 1113,21 dihydroxy 16u,17 xdimethyI- A -pregnene-B,20-dione (1.1 g.).

In a similar manner 60c,l6ot,17oz trimethyl 115,21- dihydroxy A pregnene 3,20 dione and its 21-esters were also prepared.

Example 27 A solution of 5a,11 3,2l-trihydroxy-6B-fluoro-l604,170:- dimethyl-5a-pregnane-3,20-dione (1.5 g.) was heated under reflux for 4 hours with 0.75% concentrated HCl in ethanol (75 cc.), and the cooled solution was diluted with water to give a solid which was filtered, washed neutral and dried. Crystalliaztion from acetone/hexane gave 60:- fiuoro 16a,17a-dimethyl 21 hydroxy-A -pregnadiene-3,20-dione (0.98 g.). Acetylation with acetic anhydride in pyridine gave the 21-acetate.

In a similar manner 6a,1601,17a-trimethyl-2l-hydroxy- A -pregnadiene-3,20-dione and its 21-acetate were prepared.

Example 28 A solution of 6u-fiuoro-16a,17ot-dimethyl-21-hydroxy- A -pregnadiene-3,20-dione 21-acetate (4 g.) and di- 1 5 chlorodicyanobenzoquinone (3.7 g.) in benzene (80 cc.) was heated under reflux for 24 hours. The mixture was filtered and the filtrate was concentrated and run through a short column of alumina and washed through with more benzene. The combined eluate were evaporated to dryness under reduced pressure and crystallized from acetone/hexane to give 6a-fluoro 16,17a dimethyl-Zl-hydroxy- A -pregnatriene-3,ZO-dione acetate (2.9 g.).

In a similar manner 6a,16a,17a-trimethyl-21-hydroxy- A -pregnatriene-3,20-dione acetate was prepared.

Example 29 A solution of 9ot-fluoro-115,21-dihydroxy-16u,17a-dimethyl A pregnene-3,20-dione 21-acetate (0.9 g.) and chloranil (1.0 g.) in t-butyl alcohol (30 cc.) was heated under reflux for 4 hours and then concentrated under reduced pressure. The residue was dissolved in methylene chloride, filtered, and the solution washed with 0.5 N sodium hydroxide solution and then with water to neutrality. The solution was concentrated and passed down a short column of alumina and washed through with methylene chloride. The eluate and washings were evaporated to dryness and the residue crystallized from acetone/hexane to give 9oc-fll1010 115,21 dihydroxy-16a,17a-dimethyl-A pregnadiene-3,20-dione 21-acetate (0.3 g.).

Hydrolysis with 1.1 molar equivalents of sodium hydroxide in methanol in an atmosphere of nitrogen gave the free 21-hydroxy compound.

In a similar manner the following compounds were prepared:

6,9a-difluoro 115,21 dihydroxy-16oz,Hot-dimethyl- A -pregnadiene3,20-dione and its 21 acetate.

6,16oz,17oc trimethyl-9a-fiuoro 115,21 dihydroxy- A -pregnadiene-3,20-dione and its 2l-acetate.

Example 30 A solution of 9u-fluoro 115,21 dihydroxy-1611,17- dimethyl-A y -pregnadiene-3,20-dione 2l-acetate (0.5 g.) and dichlorodicyanobenzoquinone (0.45 g.) in benzene (20 cc.) was heated under reflux for hours, cooled and filtered. The filtrate was passed down a column of alumina and washed through with more benzene. The combined eluates were evaporated to dryness and the residue crystallized from acetone/cyclohexane to give 9oc-flllOIO-11/3, 21 dihydroxy l6a,17oc dimethyl A pregnatriene- 3,20-dione 21-acetate (0.18 g.).

Hydrolysis with 1.1 molar equivalents of sodium hydroxide in methanol under nitrogen gave the free 21-hydroxy compound.

The following compounds were prepared in a similar manner:

6,9a-difluoro 115,21 dihydroxy l6oc,17ot dimethyl- A -pregnatriene-3,20-dione and its 21 acetate.

6,16a,17 x trimethyl 9m fluoro-115,21-dihydroxy- A -pregnatriene-3,20-dione and its acetate.

Example 31 A variety of monoesters of 900-1111010-1113,21-(111'1Yd10XY- 16m,17a-dimethyl A pregnadiene 3,20 dione described in Example 6 were prepared according to known procedures by reacting the free hydroxy compound with the appropriate acylating agent. These include such esters as the formate, acetate, propionate, isobutyrate, pivalate, hexanoate, isovalerate, decanoate, palmitate, phenylpropionate and hemisuccinate.

Reaction with pyridine sulphur trioxide complex in pyridine gave the pyridinium salt of the hemisulphate ester which, by interaction with the appropriate metal salt, was converted into the sodium, potassium and calcium salts of the hemisulphate ester.

In the same manner the 21-esters of the following compounds Were prepared:

6a,l6a,17a trimethyl 9oz fluoro-115,21-dihydroxy- A -pregnadiene-3,ZO-dione.

6a,9u-difluoro 115,21 dihydroxy-16a,17 x-dimethyl- A -pregnadiene-3,20-dione.

9a-fluoro 115,21 dihydroxy 1611,17 dimethyl- A -pregnen-3,20-dione.

6oz fluoro 115,21 dihydroxy-16m,17u-dimethyl-A pregnene-3,20-dione.

6a,9ot difiuoro 115,21 dihydroxy-16a,Hot-dimethyl- A -pregnene-3,2O-dione.

6a,l6a,17u-trimethyl 115,21 dihydroxy-A -pregnene- 3,20-dione.

60t,160t,170t trimethyl 9a fluoro-115,21-dihydroxy- A -pregnene-3,20-dione.

6a,fluoro 115,21 dihydroxy-16a,17a-dimethy1-A pregnene-3,20-dione.

60c,16cx.,170t trimethyl 9oz fluoro 115,21 dihydroxy- A -pregnadiene-3,2O-dione.

6ot,l6oz,l7oz -trimethy1 115,21 dihydroxy A -pregnene-3,20-dione.

9a fluoro 115,21 dihydroxy-16a,17a-dimethyl-A pregnene-3,20-dione.

6,9ot-difiuoro-115,21 dihydroxy 16a,17 x dimethyl- A -pregnadiene-3,20-dione.

6,16a,17a-trimethyl- 9a fluoro 115,21 dihydroxy- A -pregnadiene-3,20-dione.

9a-fiuoro-115,21 dihydroxy 16a,17adimethyl-A pregnatriene-3,20-dione.

6,9a-difluoro 115,21 dihydroxy 1611,1704 dimethyl- A -pregnatriene-3,20-dione.

6,l6a,170z trimethyl 9a fluoro 115,21-dihydroxy- A -triene-3,20-dione.

9a-fluoro 115,21 dihydroxy 1610c methyl-17a-ethyl- A -pregnadiene-3,2O-dione.

9a fluoro 115,21 dihydroxy 16a-ethyl-17a-methyl- A -pregnadiene-3,20-dione.

What is claimed is:

1. Process for the introduction of a 17a-alkyl substituent into a 20-keto-steroid of the pregnane series comprising reacting a A -20-Grignard enolate of a 20-ketosteroid of the pregnane series with a compound of the formula:

wherein R is a saturated aliphatic hydrocarbon group, having 1-4 carbon atoms, and X is a halogen atom.

2. Process according to claim 1 in which the starting product is the ZO-Grignard enolate of the corresponding 16a-alkyl-A -20hydroxy compound.

3. Process according to claim 1 in which the reaction takes place in an aprotic solvent with a low dielectric constant.

4. Novel pregnane compounds of the formula:

CHzZ

in which R is a saturated aliphatic hydrocarbon group having 1-4 carbon atoms,

R is selected from the group consisting of hydrogen and a saturated aliphatic hydrocarbon radical having 1-4 carbon atoms,

R is selected from the group consisting of hydrogen, a

methyl group and halogen;

X is selected from the group consisting of hydrogen and fluorine;

Z is selected from the group consisting of H, OH and OAcyl; and

17 18 C C and C 43 are selected from the group consisting X is selected from the group consisting of hydrogen and of a saturated and an unsaturated bond. fluorine; and 5. Novel pregnane compounds of the formula: R is selected from the group consisting of hydrogen and 01120}; acyl derived from a member selected from the group consisting of an inorganic acid and an organic carboxylic acid having from 1 to 18 carbon atoms. "-0113 H0 -CH3 References Cited UNITED STATES PATENTS I 10 3,232,839 2/1966 Kuslich et a1. 167-77 OTHER REFERENCES Engel et 211.: Can. J. Chem., vol. 39, No. 9, 1961.

wherein C -C is selected from the group consisting of a saturated 15 ELBERT L. ROBERTS, Primary Examiner and an unsaturated bond;

(222 2? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,520,908 Dated July 21, 1970 nv CQLIN LESLIE HEWETT ET AL.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

' Claim 4, change the structural formula to read:

R L 1 0 "l no Claim 5, change the structural formula to read:

CH OR L=O I CH3 I I CH 0 KIN SEMI Amen Edward M-Ikwhqh. VIII-HA! I. JR.

Commissioner of Patents 

